[go: up one dir, main page]

US7288549B2 - Heterocyclic compounds, method for preparing same and use thereof as medicines, in particular as antibacterial agents - Google Patents

Heterocyclic compounds, method for preparing same and use thereof as medicines, in particular as antibacterial agents Download PDF

Info

Publication number
US7288549B2
US7288549B2 US10/480,019 US48001904A US7288549B2 US 7288549 B2 US7288549 B2 US 7288549B2 US 48001904 A US48001904 A US 48001904A US 7288549 B2 US7288549 B2 US 7288549B2
Authority
US
United States
Prior art keywords
stage
tetrahydro
methano
oxo
molecular formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related, expires
Application number
US10/480,019
Other languages
English (en)
Other versions
US20050245505A1 (en
Inventor
Joseph Aszodi
Maxime Lampilas
Branislav Musicki
David Alan Rowlands
Pascal Colette
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Entasis Therapeutics Ltd
Original Assignee
Aventis Pharma SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Aventis Pharma SA filed Critical Aventis Pharma SA
Assigned to AVENTIS PHARMA S.A. reassignment AVENTIS PHARMA S.A. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ROWLANDS, D.A., ASZODI, J., COLETTE, P., MUSICKI, B., LAMPILAS, M.
Publication of US20050245505A1 publication Critical patent/US20050245505A1/en
Assigned to NOVEXEL reassignment NOVEXEL ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: AVENTIS PHARMA S.A.
Priority to US11/810,981 priority Critical patent/US8148540B2/en
Application granted granted Critical
Publication of US7288549B2 publication Critical patent/US7288549B2/en
Assigned to ENTASIS THERAPEUTICS LIMITED reassignment ENTASIS THERAPEUTICS LIMITED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ASTRA ZENECA HOLDING FRANCE
Assigned to ASTRA ZENECA HOLDING FRANCE reassignment ASTRA ZENECA HOLDING FRANCE MERGER (SEE DOCUMENT FOR DETAILS). Assignors: NOVEXEL
Adjusted expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to new heterocyclic compounds, their preparation and their use as medicaments, in particular as anti-bacterial agents.
  • a subject of the invention is the compounds corresponding to the following formula (I):
  • R1 represents a hydrogen atom, a COOH, CN, COOR, (CH 2 )n′R 5 , CONR 6 R 7 or
  • R is chosen from the group constituted by an alkyl radical containing 1 to 6 carbon atoms, optionally substituted by a pyridyl radical, a —CH 2 -alkenyl radical containing in total 3 to 9 carbon atoms, a (poly)alkoxyalkyl group containing 1 to 4 oxygen atoms and 3 to 10 carbon atoms, an aryl radical containing 6 to 10 carbon atoms or an aralkyl radical containing 7 to 11 carbon atoms, the ring of the aryl or aralkyl radical being optionally substituted by an OH, NH 2 , NO 2 , alkyl radical containing 1 to 6 carbon atoms, an alkoxy radical containing 1 to 6 carbon atoms or by one or more halogen atoms,
  • R 5 is chosen from the group constituted by a COOH, CN, OH, NH 2 , CO—NR 6 R 7 , COOR, OR, OCOH, OCOR, OCOOR, OCONHR, OCONH 2 , OSO 2 R, NHR, NHCOR, NHCOH, NHSO 2 R, NH—COOR, NH—CO—NHR, NH—CO—NH 2 or N 3 radical, R being defined as above,
  • R 6 and R 7 are chosen from the group constituted by a hydrogen atom, an alkyl radical containing 1 to 6 carbon atoms, an aryl radical containing 6 to 10 carbon atoms and an aralkyl radical containing 7 to 11 carbon atoms and an alkyl radical containing 1 to 6 carbon atoms substituted by a pyridyl radical,
  • n′ is equal to 1 or 2
  • R 3 and R 4 together form a phenyl or a heterocycle of aromatic character with 5 or 6 vertices containing 1 to 4 heteroatoms chosen from nitrogen, oxygen and sulphur, and optionally substituted by one or more R′ groups, R′ being chosen from the group constituted by a hydrogen atom and the alkyl radicals containing 1 to 6 carbon atoms, optionally substituted by one or more hydroxy, oxo, halogen or cyano radicals or by a nitro radical, alkenyl containing 2 to 6 carbon atoms, halogen, amino, OH, protected OH, —OR, —NHCOH, —NHCOR, NHCOOR, COOH, —COOR, —C(C 6 H 5 ) 3 and —CH 2 —CH 2 —S(O)m-R radicals, R being as defined previously and m being equal to 0, 1 or 2,
  • R 4 represents a hydrogen atom or a (CH 2 ) n′1 R 5 group, n′1 being equal to 0, 1 or 2 and R 5 being as defined above,
  • R 1 and R 3 together form a phenyl or an optionally substituted heterocycle, as defined above,
  • R 2 is chosen from the group constituted by a hydrogen atom, a halogen atom and the R, S(O) m R, OR, NHCOR, NHCOOR and NHSO 2 R radicals, m and R being as defined previously,
  • X represents a divalent group —C(O)—B— linked to the nitrogen atom by the carbon atom
  • R 8 is chosen from the group constituted by a hydrogen atom, an OH, R, OR, Y, OY, Y 1 , OY 1 , Y 2 , OY 2 , Y 3 , O—CH 2 —CH 2 —S(O)m-R, SiRaRbRc and OSiRaRbRc radical, Ra, Rb and Rc representing individually a linear or branched alkyl radical containing 1 to 6 carbon atoms or an aryl radical containing 6 to 10 carbon atoms, and R and m being as defined previously.
  • Y is chosen from the group constituted by the COR, COOR, CONH 2 , CONHR, CONHOH, CONHSO 2 R, CH 2 COOH, CH 2 COOR, CH 2 CONHOH, CH 2 CONHCN, CH 2 tetrazole, protected CH 2 tetrazole, CH 2 SO 3 H, CH 2 SO 2 R, CH 2 PO(OR) 2 , CH 2 PO(OR)(OH), CH 2 PO(R)(OH) and CH 2 PO(OH) 2 radicals,
  • Y 1 is chosen from the group constituted by the SO 2 R, SO 2 NHCOH, SO 2 NHCOR, SO 2 NHCOOR, SO 2 NHCONHR, SO 2 NHCONH 2 and SO 3 H radicals,
  • Y 2 is chosen from the group constituted by the PO(OH) 2 , PO(OR) 2 , PO(OH)(OR) and PO(OH)(R) radicals,
  • Y 3 is chosen from the group constituted by the following radicals: tetrazole, tetrazole substituted by the R radical, squarate, NH or NR tetrazole, NH or NR tetrazole substituted by the R radical, NHSO 2 R and NRSO 2 R, R being defined as above,
  • n is equal to 1 or 2.
  • a subject of the invention is also the salts of these compounds which can be obtained with bases or mineral or organic acids.
  • the asymmetrical carbon atoms contained in the compounds of formula (I) can, independently of one another, have the R, S or RS configuration and therefore a subject of the invention is also the compounds of formula (I) in the form of pure enantiomers or pure diastereoisomers or in the form of a mixture of enantiomers in particular of racemates, or mixtures of diastereoisomers.
  • alkyl radical containing 1 to 6 carbon atoms is meant the methyl, ethyl, propyl, isopropyl, as well as butyl, pentyl or hexyl linear or branched radical.
  • aryl radical containing 6 to 10 carbon atoms is meant a phenyl or naphthyl radical.
  • aralkyl radical containing 7 to 11 carbon atoms is meant a benzyl, phenethyl or methylnaphthyl radical.
  • alkoxy radical containing 1 to 6 carbon atoms is meant in particular the methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy or tert-butoxy radical.
  • halogen radical or by halogen atom is meant fluorine, chlorine, bromine or iodine.
  • squarate radical is meant the radical of formula:
  • heterocycle of aromatic character is meant in particular those chosen from the following list, the two bonds symbolizing the junction with the nitrogenous ring (R 3 R 4 or R 1 R 3 ):
  • salts of acids of the products of formula (I) there can be mentioned amongst others, those formed with mineral acids, such as hydrochloric, hydrobromic, hydroiodic, sulphuric or phosphoric acids or with organic acids such as formic, acetic, trifluoroacetic, propionic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic acids, alkanesulphonic acids, such as methane and ethane sulphonic acids, arylsulphonic acids such as benzene and paratoluenesulphonic acids.
  • mineral acids such as hydrochloric, hydrobromic, hydroiodic, sulphuric or phosphoric acids
  • organic acids such as formic, acetic, trifluoroacetic, propionic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, as
  • salts of bases of the products of formula (I) there can be mentioned amongst others, those formed with mineral bases such as, for example, sodium, potassium, lithium, calcium, magnesium or ammonium hydroxide or with organic bases such as, for example, methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N,N-dimethylethanolamine, tris(hydroxymethyl)amino methane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine, N-methylglucamine, or also the salts of phosphonium, such as alkyl-phosphonium, aryl-phosphoniums, alkyl-aryl-phosphonium, alkenyl-aryl-phosphonium or the salts of quaternary ammoniums such as the salt of tetra-n-butylammonium.
  • mineral bases such as
  • n is equal to 1 as well as those in which R 2 is a hydrogen atom.
  • R1 is chosen from the group constituted by the hydrogen atom and the COOCH 3 , COOC 2 H 5 , CONH 2 , CONHCH 3 , CONHCH 2 -phenyl and CONHCH 2 -pyridyl groups.
  • a particular subject of the invention is also those in which X represents a divalent group —CO—B— in which B represents an —NR 8 —(CH 2 ) n′′ — group as defined above, in which n′′ is equal to O.
  • R8 is a Y 1 or OY 1 group, in which Y 1 is chosen from the SO 2 R, SO 2 NHCOR, SO 2 NHCOOR, SO 2 NHCONHR and SO 3 H groups and R is as defined above; or those in which the R 8 group is chosen from the group constituted by the hydrogen atom and the hydroxy, CO-phenyl, O-allyl, OPO 3 H, OPO 3 -benzyl, OCH 2 COOH and O-benzyl groups.
  • Another subject of the invention is a process allowing the preparation of the compounds of formula (I).
  • R′′ is chosen from the group constituted by an alkyl radical containing 1 to 6 carbon atoms, optionally substituted by a pyridyl radical, a —CH 2 -alkenyl radical containing in total 3 to 9 carbon atoms, an aryl radical containing 6 to 10 carbon atoms or an aralkyl radical containing 7 to 11 carbon atoms, the ring of the aryl or aralkyl radical being optionally substituted by an NO 2 , protected OH, protected NH 2 radical, an alkyl radical containing 1 to 6 carbon atoms, an alkoxy radical containing 1 to 6 carbon atoms or by one or more halogen atoms,
  • R′ 5 is chosen from the group constituted by the following radicals: a protected OH, CN, protected NH 2 , CO—NR 6 R 7 , protected COOH, COOR′′, OR′′, OCOH, OCOR′′, OCOOR′′, OCONH 2 , OCONHR′′, protected NHR′′, NHCOR′′, NHSO 2 R′′, NH—COOR′′, NH—CO—NHR′′ or
  • R′ 4 represents a hydrogen atom or a (CH 2 ) n′1 R′ 5 group, n′1 being equal to 0, 1 or 2 and R′ 5 being as defined above,
  • R′ 1 and R 3 together form a phenyl or an optionally substituted heterocycle, as defined above for R 3 and R 4 ,
  • R′ 2 is chosen from the group constituted by a hydrogen atom, a halogen atom and the R′′, S(O) m R′′, OR′′, NHCOH, NHCOR′′, NHCOOR′′ and NHSO 2 R′′ radicals, R′′ being as defined previously,
  • ZH represents an HO—(CH 2 ) n′′ , HNR′ 8 —(CH 2 ) n′′ — or HNR 8 —O— group
  • Y′ is chosen from the group constituted by the COH, COR′′, COOR′′, CONH 2 , CONHR′′, CONHSO 2 R′′, CH 2 COOR′′, protected CH 2 tetrazole, CH 2 SO 2 R′′, CH 2 PO(OR′′) 2 , protected CONHOH, protected CH 2 COOH, protected CH 2 CONHOH, protected CH 2 SO 3 , protected CH 2 PO(OR)(OH), protected CH 2 PO(R)(OH) and protected CH 2 PO(OH) 2 radicals,
  • Y′ 1 is chosen from the group constituted by the SO 2 R′′, SO 2 NHCOH, SO 2 NHCOR′′, SO 2 NHCOOR′′, SO 2 NHCONH 2 , SO 2 NHCONHR′′ and protected SO 3 H radicals,
  • Y′ 2 is chosen from the group constituted by the PO(OR′′) 2 , protected PO(OH) 2 , protected PO(OH)(OR) and protected PO(OH)(R) radicals,
  • Y′ 3 is chosen from the group constituted by the protected tetrazole, tetrazole substituted by the R′′ radical, protected squarate, protected NH tetrazole, protected NR′′ tetrazole, protected NH, NR′′ tetrazole substituted by the R′′ radical, NHSO 2 R′′ and NSO 2 R′′ radicals, R′′ being defined as above.
  • n is as defined above;
  • a reagent can be used such as phosgene, diphosgene, triphosgene, an aryl chloroformate such as phenyl or p-nitrophenyl chloroformate, an aralkyl chloroformate such as benzyl chloroformate, an alkyl or alkenyl chloroformate such as methyl or allyl chloroformate, an alkyl dicarbonate such as tert-butyl dicarbonate, carbonyl-diimidazole and their mixtures.
  • the reaction preferably takes place in the presence of a base or a mixture of bases which neutralize the acid formed.
  • a base or a mixture of bases which neutralize the acid formed.
  • It can in particular be an amine such as triethylamine, diisopropylethylamine, pyridine, dimethylaminopyridine.
  • the operation can also be carried out by using the starting product of formula II as base. It is then used in excess.
  • the product of formula II is used in the form of an acid salt, for example a hydrochloride or a trifluoroacetate.
  • amines can also be used, or also hydrides, alcoholates, amides or carbonates of alkali or alkaline-earth metals.
  • the amines can be chosen for example from the list above.
  • hydride sodium or potassium hydride can in particular be used.
  • potassium t-butylate is preferably used as alkali metal alcoholate.
  • alkali metal amide lithium bis(trimethylsilyl)amide can in particular be used.
  • carbonate sodium or potassium carbonate or bicarbonate can in particular be used.
  • the intermediate of formula III can be obtained in the form of an acid salt generated during the carbonylation reaction and in particular a hydrochloride. It is then used in the cyclization reaction in this form.
  • stage c The reactions mentioned in stage c) are generally standard reactions, well known to a person skilled in the art.
  • the reactive functions which are suitable, if appropriate, to protect are the carboxylic acid, amine, amide, hydroxy and hydroxylamine functions.
  • Protection of the acid function is in particular carried out in the form of alkyl esters, allylic esters of benzyl, benzhydryl or p-nitrobenzyl.
  • Deprotection is carried out by saponification, acid hydrolysis, hydrogenolysis, or also cleavage using soluble complexes of Palladium O.
  • Protection of the amines, heterocyclic nitrogens and amides is in particular carried out depending on the case in the form of benzylated or tritylated derivatives, in the form of carbamates, in particular of allyl, benzyl, phenyl or tertbutyl, or also in the form of silylated derivatives such as tertbutyl dimethyl, trimethyl, triphenyl or also diphenyl tertbutyl-silyl derivatives, or phenylsulphonylalkyl or cyanoalkyl derivatives.
  • Deprotection is carried out, according to the nature of the protective group, by sodium or lithium in liquid ammonia, by hydrogenolysis or using soluble complexes of Palladium O, by the action of an acid, or by the action of tetrabutylammonium fluoride or strong bases such as sodium hydride or potassium t.butylate.
  • Protection of the hydroxylamines is carried out in particular in the form of benzyl or allyl ethers.
  • Cleavage of the ethers is carried out by hydrogenolysis or using soluble complexes of Palladium O.
  • the ethers can be alkyl or alkoxyalkyl ethers, preferably methyl or methoxyethoxymethyl ethers, aryl or preferably aralkyl ethers, for example benzyl, or silylated ethers, for example the silylated derivatives mentioned above.
  • the esters can be any cleavable ester known to a person skilled in the art and preferably the acetate, propionate or benzoate or p-nitrobenzoate.
  • the carbonates can be for example methyl, tertbutyl, allyl, benzyl or p-nitrobenzyl carbonates.
  • Deprotection is carried out by means known to a person skilled in the art, in particular saponification, hydrogenolysis, the cleavage by soluble complexes of Palladium O, hydrolysis in an acid medium or also, for the silylated derivatives, treatment by tetrabutylammonium fluoride.
  • the sulphation reaction is carried out by the action of SO 3 -amine complexes such as SO 3 -pyridine or SO 3 -dimethylformamide, operating in pyridine, the salt formed, for example the pyridine salt, can then be exchanged for example by a salt of another amine, of a quaternary ammonium or of an alkali metal. Examples are provided in the experimental part.
  • the phosphation reaction is carried out for example by the action of a chlorophosphate such as dimethyl, dibenzyl or diphenyl chlorophosphate.
  • amidification reaction is carried out starting with carboxylic acid using an activation agent such as an alkyl chloroformate, EDCI or BOP by the action of ammonium hydroxide or an appropriate amine or their acid salts. Examples are provided hereafter in the experimental part.
  • acylation and sulphonylation reactions are carried out on hydroxyureas, alcohols, amines or heterocyclic nitrogens, by the action depending on the case of a halide, an appropriate carboxylic acid anhydride or sulphonic acid, where appropriate in the presence of a base.
  • a halide an appropriate carboxylic acid anhydride or sulphonic acid, where appropriate in the presence of a base.
  • the alkylation reaction is carried out by the action on the hydroxylated derivatives, the ester or ketone enolates, amines or heterocyclic nitrogens, depending on the case, of an alkyl sulphate or of an alkyl or substituted alkyl halide, substituted in particular by a free or esterified carboxy radical. Illustrations are provided hereafter in the experimental part.
  • Reduction of the acids to alcohols can be carried out by the action of a borane or via a mixed anhydride intermediate, by the action of an alkaline borohydride.
  • the mixed anhydride is prepared for example using an alkyl chloroformate.
  • the reduction of the aldehyde to alcohol is preferably carried out by the action of sodium borohydride. Illustrations are provided in the experimental part.
  • Dehydration of the amide to nitrile can be carried out under the conditions of carbonylation and cyclization reactions.
  • Oxidation of the sulphides to sulphoxide and/or sulphone can be carried out by the action of a peracid such as metachloroperbenzoic or perphthalic acid or any other reagent known to a person skilled in the art.
  • a peracid such as metachloroperbenzoic or perphthalic acid or any other reagent known to a person skilled in the art.
  • Salification by acids is, if appropriate, carried out by adding an acid in soluble phase to the compound.
  • Salification by bases can relate to the compounds comprising an acid function and in particular the compounds comprising a carboxy function, those comprising a sulphooxy function or derived from phosphoric acid or those comprising a heterocycle of acid character.
  • the operation is carried out by adding an appropriate base such as those mentioned previously.
  • the pyridinium salt is obtained directly during the action of the SO3-pyridine complex and the other salts are obtained from this pyridinium salt.
  • the operation can also be carried out by ion exchange on resin. Examples of salification by acids or by bases and including a heterocycle of acid character, are provided hereafter in the experimental part.
  • Nitration can be carried out using nitric acid or one of the metallic salts, in an acid medium.
  • Reduction of a nitro group can be carried out using sodium dithionite or also using zinc in acetic acid.
  • halogenation is meant the introduction of a halogenated substituent from a hydroxy or direct halogenation of an aromatic ring.
  • the reaction can for example be implemented by the action of iodine in the presence of triphenylphosphine, by the action of bromine in acetic acid or also iodine in the presence of C 6 H 5 I(OCOCF 3 ) 2 , or also by the reaction of an electrophilic halogenated derivative such as N-fluorosulphonylimide in the presence of a strong base.
  • reagents are known to a person skilled in the art and examples are shown below in the experimental part.
  • the thioalkylation reaction can be carried out by implementing a reagent such as methyl methylthiosulphonate in the presence of a strong base, therefore by a reaction of electrophilic type.
  • the carbamoylation reaction can be carried out by implementing a chloroformate then an amine or, if appropriate, ammonia.
  • an azido group can be carried out for example by the action of a sodium nitride on an intermediate of mesylate type.
  • the reduction of an azide group can be carried out by the action of trialkyl out triarylphosphine.
  • the aromatic halogen coupling reaction with tin derivatives is carried out using Stille's method which consists in initially forming an alkenylated derivative of an aromatic halide then reducing the alkenyl to alkyl, for example using hydrogen in the presence of a catalyst such as palladium on carbon.
  • Stille's method which consists in initially forming an alkenylated derivative of an aromatic halide then reducing the alkenyl to alkyl, for example using hydrogen in the presence of a catalyst such as palladium on carbon.
  • Dihydroxylation of the double carbon-carbon bond is carried out in particular by the action of osmium tetroxide.
  • Cleavage of the diols is preferably carried out using sodium periodate.
  • cyano is carried out by nucleophilic substitution using an alkaline cyanide.
  • the compounds of formula (I) can of course be obtained by methods which use at the start a compound of formula (II) in which R′ 1 , R′ 2 , R 3 , R 4 and HZ have the values which lead directly (without conversion) to those of the compounds that one wishes to prepare. If appropriate, those values which would contain reactive functions as mentioned above are then protected, deprotection occurring at the end of cyclization stage b or at any other opportune moment during the synthesis. The protections and deprotections are then carried out as described above.
  • a subject of the invention is also a process according to what has gone before, characterized in that the compound of formula (II) in which ZH represents an HO—(CH 2 ) n′′ — or HNR′ 8 —(CH 2 ) n′′ — group in which n′′ is equal to O, or a HNR′ 8 —O— group, is obtained by a process according to which a compound of formula (IV):
  • R′ 1 , R′ 2 , R 3 , R′ 4 and n are as defined previously, and A represents a hydrogen atom or a protective group of nitrogen, is treated with a reducing agent, in order to obtain a compound of formula (V):
  • R′ 1 , R 3 , R′ 4 and n retain their previous meaning and R9 represents a parting group, which is treated with a compound of formula Z 1 H 2 in which Z 1 represents a divalent —NR′ 8 — or —ONR′ 8 — group, R′ 8 retaining the previous meaning, then, if appropriate, with a deprotection agent of the appropriate nitrogen atom.
  • a subject of the invention is also a process according to what has gone before, characterized in that the compound of formula (II) in which ZH represents a NHR′ 8 —(CH 2 ) n′′ — group in which n′′ is equal to 0 is obtained by a process according to which a compound of formula (IV) as defined previously, is treated with a compound of formula H 2 NR′ 8 , in order to obtain a compound of formula (VII):
  • R′ 1 , R′ 2 , R 3 , R′ 4 , n′′ and R′ 8 are as defined previously, which is treated, if appropriate, with a deprotection agent of the appropriate nitrogen atom.
  • the protective group of the nitrogen is in particular one of those which are mentioned above.
  • the reducing agent is in particular an alkaline borohydride.
  • the parting group is in particular a sulphonate, for example a mesylate or a tosylate, obtained by the action of the corresponding sulphonyl chloride in the presence of a base, or a halogen, more particularly a chlorine, a bromine or an iodine, obtained for example by the action of thionyl chloride or P(C 6 H 5 ) 3 CBr 4 or PBr 3 or, in the case of an iodine atom, by the action of an alkaline iodide on a sulphonate.
  • a sulphonate for example a mesylate or a tosylate, obtained by the action of the corresponding sulphonyl chloride in the presence of a base, or a halogen, more particularly a chlorine, a bromine or an iodine, obtained for example by the action of thionyl chloride or P(C 6 H 5 ) 3 CBr 4 or
  • the deprotection agent is in particular one of those mentioned above.
  • the reducing agent which is reacted on the compound of formula (VII) is in particular a sodium cyano or acetoxyborohydride.
  • the products of general formula (I) have a very good antibiotic activity on gram (+) bacteria such as staphylococcia. Their effectiveness on gram ( ⁇ ) bacteria in particular on enterobacteria is particularly notable.
  • staphylococcia such as staphylococcal septicemias, malignant facial or cutaneous staphylococcia, pyodermitis, septic or suppurating wounds, anthrax, phlegmons, erysipelas, primitive or post-influenzal acute staphylococcias, bronchopneumonia, pulmonary suppurations.
  • These products can also be used as medicaments in the treatment of colibacillosis and associated infections, in proteus, klebsiella and salmonella infections and in other illnesses caused by gram ( ⁇ ) bacteria.
  • a subject of the present invention is, as medicaments and in particular antibiotic medicaments, the products of formula (I) as defined above as well as their salts with pharmaceutically acceptable acids and bases.
  • a more particular subject of the invention is, as medicaments, the products of formula (I) as described above in which n is equal to 1 as well as those in which R 2 is a hydrogen atom.
  • a quite particular subject of the invention is, as medicaments, the products of formula (I) in which R 3 and R 4 together form a phenyl or a heterocycle, optionally substituted, as defined previously and in particular a phenyl or a heterocycle chosen from the group constituted by thienyl, imidazolyl, furyl, pyrazolyl and triazolyl, optionally substituted.
  • R 1 is chosen from the group constituted by the hydrogen atom and the COOCH 3 , COOC 2 H 5 , CONH 2 , CONHCH 3 , CONHCH 2 -phenyl and CONHCH 2 -pyridyl groups.
  • a particular subject of the invention is also, as medicaments, the product of formula (I) in which X represents a divalent group —CO—B in which B represents an —NR 8 —(CH 2 ) n′′ — group as defined above, in which n′′ is equal to O.
  • R8 is a Y 1 or OY 1 group, in which Y 1 is chosen from the SO 2 R, SO 2 NHCOR, SO 2 NHCOOR, SO 2 NHCONHR and SO 3 H groups and R as defined above; or those in which the R 8 group is chosen from the group constituted by the hydrogen atom and the hydroxy, CO-phenyl, O-allyl, OPO 3 H, OPO 3 -benzyl, OCH 2 COOH and O-benzyl groups.
  • a subject of the invention is also the pharmaceutical compositions containing as active ingredient, at least one of the compounds according to the invention as defined above.
  • compositions can be administered by buccal, rectal, parenteral, in particular intramuscular route or by local route as a topical application on the skin and the mucous membranes.
  • compositions according to the invention can be solids or liquids and be presented in the pharmaceutical forms commonly used in human medicine, such as for example, plain or sugar-coated tablets, gelatin capsules, granules, suppositories, injectable preparations, ointments, creams, gels; they are prepared according to the usual methods.
  • the active ingredient(s) can be incorporated with the excipients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents, preservatives.
  • compositions can in particular be presented in the form of a powder intended to be dissolved extemporaneously in an appropriate vehicle, for example apyrogenic sterile water.
  • the dose administered is variable according to the condition treated, the patient in question, the administration route and the product considered. It can be, for example, comprised between 0.250 g and 10 g per day by oral route in adults with the product described in Example 1 or also comprised between 0.25 g and 10 g per day by intramuscular or intravenous route.
  • the products of formula (I) can also be used as disinfectants for surgical instruments.
  • a subject of the invention is, as new industrial products and in particular as intermediate products necessary for the preparation of the products of formula (I),
  • R′ 4 represents a hydrogen atom
  • R′ 1 and R 3 together form a phenyl
  • R′ 1 and R 3 together form an optionally substituted heterocycle as defined for R 3 and R 4 as well as their salts with acids and in particular their hydrochlorides and trifluoroacetates
  • the residue is purified by chromatography on silica, eluting with dichloromethane then with a dichloromethane/AcOEt mixture 98/2.
  • the reaction medium is heated to 70° C. and maintained for 4 hours, followed by evaporating to dryness under reduced pressure.
  • the reaction medium is kept under agitation overnight at 20° C., followed by diluting with dichloromethane, adjusting to pH 8-9 by adding 2N soda while cooling, diluting with 1 l of water and 1 l of dichloromethane, decanting, extracting several times with dichloromethane, the organic phases are collected and dried over sodium sulphate.
  • the solvent is evaporated off under reduced pressure and then purified by chromatography on silica.
  • reaction medium is agitated whilst being left to return to 20° C. over 30 minutes, followed by diluting with 200 ml of dichloromethane, washing with a 10% aqueous solution of tartaric acid, then with demineralized water and drying the organic phase over sodium sulphate.
  • the solvent is evaporated off under reduced pressure.
  • the reaction medium is cooled down to 05° C., then 10.8 ml of TEA and 5.3 ml of methane sulphonyl chloride are added successively, followed by allowing the temperature to return to 20° C. and keeping under agitation for 1 hour 20 minutes at 20° C., diluting with dichloromethane, washing with a 10% aqueous solution of tartaric acid and with demineralized water.
  • the organic phase is dried over sodium sulphate.
  • O-allylhydroxylamine 24.5 ml is added to the mesylate freshly prepared in Stage H, then they are left in contact at 0-5° C. for 72 hours, followed by diluting with dichloromethane and washing with a 10% aqueous solution of tartaric acid then with demineralized water, drying the organic phase over sodium sulphate and evaporating the solvent under reduced pressure.
  • the dry extract obtained is purified by chromatography on silica eluting with a dichloromethane/AcOEt mixture 98/2.
  • reaction medium is agitated for 2 minutes and then 1.8 ml (14.6 mmole) of diphosgene is introduced.
  • the solution is agitated at 20° C. for 1 hour, followed by diluting with AcOEt, washing with a 10% solution of tartaric acid then with water, drying the organic phase over magnesium sulphate and evaporating the solvent under reduced pressure.
  • reaction medium is left under agitation at 20° C. for 1 hour 30 minutes, then evaporation is carried out without heating under reduced pressure.
  • the dry extract obtained is purified by chromatography on silica eluting progressively with a dichloromethane/acetone mixture containing 0.1% by volume of TEA: 100/0 then 80/20 and 50/50.
  • the solution obtained is passed through a DOWEX 50WX8 resin column in the Na + form, eluting with water containing 10% THF.
  • Agitation is carried out for 30 minutes at 80° C. then for 3 hours at 50° C.
  • the solvent is evaporated off under reduced pressure.
  • the solvent is evaporated off under reduced pressure and purifification is carried out by chromatography on silica eluting with a dichloromethane/AcOEt mixture 1/1.
  • reaction medium is left under agitation for 1 hour, then diluted in 250 ml of dichloromethane, followed by washing with a 10% solution of tartaric acid, drying the organic phase over magnesium sulphate and evaporating the solvent under reduced pressure.
  • the medium is left to react for 5 hours then an aqueous solution of sodium hydrogen carbonate is added and agitation is carried out for 15 minutes, followed by extracting with dichloromethane and washing with water.
  • the organic phase is dried over magnesium sulphate.
  • the solvent is evaporated off under reduced pressure.
  • the product obtained is purified by chromatography on silica eluting successively with a dichloromethane/AcOEt mixture 9/1, then 8/2.
  • the medium is left to react for 30 minutes at 0° C., then left to return to ambient temperature.
  • reaction medium is left under agitation for a few minutes, then the aqueous phase is evaporated under reduced pressure and the residue is dissolved in 40 ml of a dichloromethane/ethanol mixture 9/1.
  • reaction medium is left to return to ambient temperature and reacted for 30 minutes, followed by diluting with AcOEt, washing with water and drying the organic phase over magnesium sulphate.
  • the solvent is evaporated off under reduced pressure.
  • the residue is purified by chromatography on silica eluting with a dichloromethane/AcOEt mixture 1/1 containing 0.1% by volume of TEA.
  • reaction medium is left to react for 4 hours, then diluted with dichloromethane.
  • the solvent is evaporated off under reduced pressure, followed by taking up in dichloromethane, washing with water and drying the organic phase over magnesium sulphate.
  • the solution obtained is passed through a DOWEX 50WX8 resin column in Na + form, eluting with water containing 10% THF.
  • the solvent is evaporated off under reduced pressure followed by diluting with dichloromethane, washing with a 10% aqueous solution of tartaric acid then with demineralized water, drying the organic phase over sodium sulphate and evaporating the solvent under reduced pressure.
  • reaction medium is poured into water saturated with sodium hydrogen carbonate. Agitation is carried out for 45 minutes, followed by decanting, washing the organic phase with demineralized water and drying over sodium sulphate.
  • reaction medium is left to return to ambient temperature and agitation is carried out for 1 hour.
  • the solvents are evaporated off under reduced pressure, followed by diluting with water, neutralizing with 40 ml of ammonium hydroxide and extracting with dichloromethane after having saturated the aqueous phase with sodium chloride. In this way 38.97 g of a yellow oil is recovered which is purified by chromatography on silica, eluting with a dichloromethane/AcOEt mixture 95/5.
  • reaction medium is left to return to ambient temperature and agitation is carried out for 1 hour, followed by diluting the reaction mixture with 1 l of ethyl acetate then washing the organic phase three times with 500 ml of water.
  • the solvent is evaporated off under reduced pressure.
  • reaction medium is cooled down to ⁇ 20° C. and 71 ⁇ l of 2,6-lutidine and 78 ⁇ l of isobutyl chloroformate are added.
  • the solvent is evaporated off under reduced pressure, followed by taking up in 50 ml of dichloromethane, washing with water and drying the organic phase over magnesium sulphate.
  • the solvent is evaporated off under reduced pressure.
  • the 1-propenyltriphenylphosphonium salt of trans-3-oxo-N-(phenylmethyl)-4-(sulphooxy)-2,3,4,5-tetrahydro-2,5-methano-1H-2,4-benzodiazepine-1-carboxamide is recovered which is dissolved in 1 ml of water containing 10% THF.
  • the solution obtained is passed through a DOWEX 50WX8 resin column in Na + form, eluting with water containing 10% THF.
  • the intermediate hydroxyurea precipitates.
  • the precipitate is filtered, then redissolved in 4 ml of pyridine and 100 mg of the SO 3 -pyridine complex is added.
  • the reaction medium is left under agitation at 20° C. for 4 hours, then concentrated under vacuum.
  • reaction medium is agitated for 15 minutes at 20° C., followed by washing three times with 5 ml of AcOEt, treating with 60 mg of n-Bu 4 N + HSO 4 ⁇ , adjusting the pH to 5 with a saturated solution of sodium hydrogen carbonate and extracting 8 times with 5 ml of AcOEt.
  • the extracted phases are combined, dried and the solvent is evaporated off under vacuum.
  • the corresponding yield is 70.1%.
  • the catalyst is filtered, followed by washing with ethanol and the solvent is evaporated off under reduced pressure.
  • the product crystallizes from ether.
  • the reaction medium is left to react for 3 hours 30 minutes.
  • reaction medium is left to react overnight, then filtered and the solvent is evaporated off under reduced pressure.
  • reaction medium is cooled down to 0° C. and 1.3 ml of N,N diisopropylethyamine then 34 mg of DMAP, 153 ml of carbon tetrachloride and 1.5 ml of dibenzylphosphite are added.
  • reaction medium is left to return to ambient temperature, then poured into a heptane/AcOEt mixture 33/66 and the organic phase is washed with a 1M aqueous solution of NaH 2 PO 4 and dried over magnesium sulphate.
  • the solution is cooled down to ⁇ 8° C. and 0.83 ml of TEA in solution in 1 ml of dichloromethane is added.
  • reaction medium is maintained under agitation at 0° C. for 2 hours, followed by pouring into water, extracting with AcOEt, washing with water and drying over magnesium sulphate. After evaporating the solvent under reduced pressure, approximately 300 mg of an oil is obtained which is purified by chromatography on silica eluting with AcOEt.
  • reaction medium is left under agitation at 20° C. for 1 hour, then 1 ml of dichloromethane is added and agitation is continued at ambient temperature for 2 hours.
  • the solvent is evaporated off under reduced pressure.
  • reaction medium is left under agitation for 4 hours at 20° C., followed by diluting with AcOEt, washing with a 10% aqueous solution of tartaric acid %, then with a phosphate buffer at pH 7 and with a saturated aqueous solution of sodium chloride.
  • reaction medium 15 mg of Pd/C catalyst at 10% by weight is added.
  • the reaction medium is placed under a hydrogen atmosphere at normal pressure and left to react at ambient temperature for 30 minutes.
  • the catalyst is rinsed with AcOEt.
  • the solvent is evaporated off under reduced pressure in order to collect 25 mg of product which is washed with 0.5 ml of ethyl ether.
  • the catalyst is rinsed with methanol.
  • the filtrate solvent is evaporated in order to collect 4 g of an oil which is taken up in dichloromethane, filtered again and the solvent is evaporated off under reduced pressure.
  • reaction medium is cooled down to 0-5° C. and 14.6 ml of a solution of hydrogen chloride in AcOEt at 4.6 mol/l is added at this temperature.
  • the temperature of the reaction medium is left to rise to 20° C. over one hour, then the solvent is evaporated off under reduced pressure.
  • the hydrochloride crystallizes from ethyl ether.
  • the catalyst is rinsed with AcOEt.
  • the reaction medium is left under agitation at 20° C. for 6 hours.
  • the aqueous phase is washed 3 times with 15 ml of AcOEt.
  • the product collected is lyophilized.
  • reaction medium is cooled down to 0° C., then 332 ml of a 5.5 N solution of hydrochloric acid in AcOEt is added.
  • the reaction medium is agitated for 1 hour 30 minutes at ambient temperature, followed by filtering and washing with ether.
  • the suspension is agitated for 45 minutes, then the ethanol is evaporated off under reduced pressure.
  • the residue is solubilized in AcOEt, then the organic phase is washed with water, then dried over magnesium sulphate, filtered and the solvent is evaporated off under reduced pressure.
  • the solvent is evaporated off under reduced pressure and the residue is passed through a column of DOWEX 50WX8 resin in Na + form, eluting with water containing 10% THF.
  • the product After evaporating the solvent under reduced pressure, the product is solubilized in acetone and the sodium sulphate is eliminated by filtration. The solvent is then evaporated off under reduced pressure and the product crystallizes from ethyl ether.
  • reaction medium is left to return to ambient temperature over two hours, then 1 liter of dichloromethane and 354 ml of a 10% aqueous solution of tartaric acid are added successively.
  • the reaction medium is agitated vigorously followed by decanting and reextracting with dichloromethane.
  • reaction medium is left to react for 15 minutes at ⁇ 78° C., then carbon dioxide in excess is introduced over 10 minutes, then the medium is left to return to ambient temperature.
  • the temperature is lowered to 10° C., then 1.04 g of NaBH 3 CN is added and agitation is carried out at ambient temperature for 7 hours.
  • reaction medium is then poured into a mixture of a saturated solution of sodium hydrogen carbonate in water and AcOEt.
  • Agitation is carried out for 40 minutes until there is no more release of gas, followed by decanting and extracting 4 times with AcOEt.
  • the organic phase is dried over magnesium sulphate, rinsed then the solvent is evaporated off under reduced pressure.
  • the mixture is agitated for 1 hour 30 minutes at a temperature of 10-15° C.
  • the solution is heated under reflux for 5 hours.
  • the mixture is cooled down to ambient temperature and the precipitate which forms is washed with ethanol, filtered and dried under reduced pressure.
  • reaction mixture is poured into 600 ml of water, then the precipitate formed is separated, washed with water and dried under reduced pressure.
  • reaction medium is cooled down to ⁇ 20° C., then 6.1 g (50 mmoles) of 4-dimethylaminopyridine and 7.11 ml (50 mmoles) of benzyl chloroformate in solution in 35 ml of THF are added.
  • reaction medium is then left to return to ambient temperature over one hour, followed by pouring into 300 ml of water containing ice, extracting with AcOEt, washing 3 times with water, then the organic phases are reunited and dried over sodium sulphate.
  • the solvent is evaporated off under reduced pressure.
  • the solution is cooled down to 0° C. and 140 ⁇ l of diphosgene (1.16 mmoles) is added.
  • reaction medium is left to return to ambient temperature and a solution of 840 ⁇ l of TEA in 8 ml of acetonitrile is added.
  • the solution is agitated overnight at ambient temperature.
  • the solvent is evaporated off under reduced pressure, followed by redissolving in AcOEt, washing with water, decanting, filtering and drying the organic phase over sodium sulphate.
  • the solvent is evaporated off under reduced pressure.
  • reaction medium is left in contact for 30 minutes at 0-5° C., then for 40 minutes at ambient temperature.
  • the solid After filtering, the solid is rinsed with AcOEt, then the filtrate is diluted with 400 ml of AcOEt, followed by washing successively with a saturated aqueous solution of sodium hydrogen carbonate, then with a 10% aqueous solution of tartaric acid and with water saturated in sodium chloride.
  • the organic phase is decanted and dried over magnesium sulphate, then the solvent is evaporated off under reduced pressure.
  • the reaction medium is heated at 60° C. for 9 hours.
  • reaction medium is agitated for 1 hour 30 minutes, then poured into water, followed by extracting three times with a heptane/AcOEt mixture 2/8, the organic phase is washed with water, separated and dried over magnesium sulphate.
  • the residue is purified on silica eluting with a dichloromethane/acetone mixture 95/5.
  • reaction medium is cooled down to 0° C., then 0.52 g of NaBH 4 is added, then the medium is left to react for one hour at 0° C.
  • reaction medium is cooled down to ⁇ 10° C., 17.5 ml of SOCl 2 is added, then the medium is left to react for 30 minutes at ⁇ 10° C. and then left to return to ambient temperature.
  • the reaction medium is left to react overnight at ambient temperature.
  • the residue is solubilized in 200 ml of an AcOEt/heptane mixture 2/1, followed by washing with a 1M solution of NaH 2 PO 4 , separating the organic phase and drying over magnesium sulphate.
  • the solvent is evaporated off under reduced pressure.
  • the residue is solubilized in a heptane/AcOEt mixture 10/20, the organic phase is washed with a 1M aqueous solution of NaH 2 PO 4 and the organic phase is dried over magnesium sulphate.
  • the solvent is evaporated off under reduced pressure.
  • reaction medium is left to react at ambient temperature for 45 minutes, then toluene is added and the solvent is evaporated off under reduced pressure.
  • reaction medium is left to react for 1 hour at ambient temperature, followed by extracting with a heptane/AcOEt mixture 10/20, washing with a 1M solution of NaH 2 PO 4 , the organic phase is separated and dried over magnesium sulphate.
  • the solvent is evaporated off under reduced pressure.
  • reaction medium is cooled down to 0° C. and 1.98 g of sodium cyanoborohydride is added by portions of 0.33 g every 30 minutes, then the reaction medium is left to react at ambient temperature for 30 minutes.
  • reaction medium is neutralized with a saturated solution of sodium bicarbonate, followed by extracting with an AcOEt/heptane mixture, drying the organic phase over magnesium sulphate and the solvent is evaporated off under reduced pressure.
  • the residue is purified by chromatography on silica eluting with a dichloromethane/acetone mixture 90/10.
  • reaction medium is cooled down to 0° C. and 17.5 ml of hydrogen chloride in 5.3 N solution in AcOEt is added.
  • reaction medium is left to react under agitation for one hour and 30 minutes at ambient temperature.
  • the solvent is evaporated off under reduced pressure.
  • the crystallized product obtained is solubilized in 900 ml of acetonitrile, then after cooling down to 0° C., 5.22 ml of TEA is added.
  • the crude product obtained is purified by chromatography on silica eluting with a toluene/isopropanol mixture 80/20.
  • reaction medium is brought to 0° C., then 0.120 ml of TEA is added.
  • reaction medium is returned to ambient temperature, diluting with ice, AcOEt is added, then ammonium hydroxide is added, whilst cooling.
  • reaction medium is poured into a water and dichloromethane mixture, followed by extracting twice with dichloromethane, washing twice with water, the organic phases are combined and dried over sodium sulphate, then the solvent is evaporated off under reduced pressure.
  • reaction medium is taken to 80° C. for 6 hours, left to return to ambient temperature, then 1.3 ml of terbutyl glycinate is added and taken to 80° C. for 4 hours 30 minutes.
  • reaction medium is left to return to ambient temperature and poured into an ice and sulphuric ether mixture, followed by extracting once with ether, washing the ethereal phase 4 times with water, drying the organic phase over sodium sulphate, then filtering and the solvent is evaporated off under reduced pressure.
  • the crude product is taken up in AcOEt, followed by washing with a 10% aqueous solution of tartaric acid then twice with water and then with a saturated aqueous solution of sodium hydrogen carbonate, drying the organic phase over sodium sulphate, filtering and the solvent is evaporated off under reduced pressure.
  • reaction medium is cooled down to 0° C. and 2.4 ml of trifluoroacetic anhydride is added.
  • reaction medium is left in contact for 2 hours 30 minutes, then poured into an ice/ammonium hydroxide/dichloromethane mixture, followed by washing with water, extracting with dichloromethane, drying the organic phases over sodium sulphate, filtering and the solvent is evaporated off under reduced pressure.
  • reaction medium is cooled down to 0° C. and 40 ml of trifluoroacetic acid is introduced rapidly, followed by leaving to rise to ambient temperature then leaving under agitation for 4 hours.
  • the solvent is evaporated off under reduced pressure.
  • the product is dissolved in AcOEt, washed successively with a dilute solution of ammonium hydroxide then with a saturated aqueous solution of NaH 2 PO 4 .
  • the reaction medium is cooled down to 0° C. and a solution of 480 ⁇ l of oxalyl chloride in 2 ml of dichloromethane is introduced.
  • reaction medium After the end of gas evolution, the reaction medium is left to return to ambient temperature. After the end of a second gas evolution, the solvent is evaporated off under reduced pressure.
  • the acid chloride prepared in Stage F put into solution in 30 ml of chlorobenzene beforehand is introduced into a flask placed nitrogen atmosphere.
  • reaction medium is taken to 90° C., then 12 ml of a 1M solution of boron trichloride in dichloromethane is added rapidly.
  • reaction medium is maintained under reflux for 5 minutes then poured into an ice/AcOEt mixture, followed by extracting twice with AcOEt and washing with salt water. The organic phases are combined, dried over sodium sulphate, filtered then the solvent is evaporated off under reduced pressure.
  • reaction medium is cooled down to ⁇ 10° C., then 2.18 g of (BOC) 2 O and 1.5 ml of TEA are added.
  • the operation is repreated twice and the reaction medium is agitated for 2 hours at ⁇ 10° C., followed by diluting with AcOEt, washing with a saturated solution of sodium chloride, separating, drying the organic phase over sodium sulphate, filtering and the solvent is evaporated off under reduced pressure.
  • the pH is adjusted to approximately 2 using a solution of hydrogen chloride in methanol.
  • the reaction medium is agitated for two hours at ambient temperature, diluting with dichloromethane, an aqueous solution of sodium hydrogen carbonate is added in order to adjust the pH to 9, followed by washing with salt water, extracting the aqueous phases with dichloromethane, separating, drying the organic phases over sodium sulphate, filtering and the solvent is evaporated off under reduced pressure.
  • reaction medium is cooled down to 0° C., then 24 ml of hydrogen chloride in solution in AcOEt at 4 moles/l is added.
  • the reaction medium is left in contact for 3 hours.
  • the solvent is evaporated off under reduced pressure, followed by taking up in AcOEt, sodium hydrogen carbonate is added, then water. After separating, the organic phase is dried over sodium sulphate, filtered, then the solvent is evaporated off under reduced pressure.
  • the reaction medium is heated at 70° C. for 6 hours and 30 minutes, then left to return to 20° C. and the insolubles are eliminated by filtration, followed by partially concentrating under reduced pressure, taking up in 550 ml of AcOEt, washing with water, then with a saturated solution of sodium chloride.
  • the organic phase is dried over sodium sulphate, filtered and the solvent is evaporated off under reduced pressure.
  • the 75 g of crude product is introduced into 300 ml of ether, then 33 ml of cyclohexylamine (0.29 mole) is added dropwise at 20° C.
  • the salt having precipitated filtration is carried out followed by washing twice with 50 ml of ether.
  • the product obtained is redissolved in 200 ml of water, then 36 ml of 6N hydrochloric acid is added dropwise at 20° C., followed by decanting and extracting the aqueous phase twice with 300 ml of AcOEt.
  • aqueous phases are combined and washed with water, then with a saturated solution of sodium chloride, followed by filtering and drying the organic phase over magnesium sulphate.
  • the solvent is evaporated off under reduced pressure.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
US10/480,019 2001-06-08 2002-06-04 Heterocyclic compounds, method for preparing same and use thereof as medicines, in particular as antibacterial agents Expired - Fee Related US7288549B2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US11/810,981 US8148540B2 (en) 2001-06-08 2007-06-07 Heterocyclic compounds, their preparation and their use as medicaments, in particular as anti-bacterial agents

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR0107520A FR2825705B1 (fr) 2001-06-08 2001-06-08 Nouveaux composes heterocycliques, leur preparation et leur utilisation comme medicaments, notamment comme anti-bacteriens
FR01/07520 2001-06-08
PCT/FR2002/001877 WO2002100860A2 (fr) 2001-06-08 2002-06-04 Composes heterocycliques, leur preparation et leur utilisation comme medicaments, notamment comme anti-bacteriens

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US11/810,981 Division US8148540B2 (en) 2001-06-08 2007-06-07 Heterocyclic compounds, their preparation and their use as medicaments, in particular as anti-bacterial agents

Publications (2)

Publication Number Publication Date
US20050245505A1 US20050245505A1 (en) 2005-11-03
US7288549B2 true US7288549B2 (en) 2007-10-30

Family

ID=8864102

Family Applications (2)

Application Number Title Priority Date Filing Date
US10/480,019 Expired - Fee Related US7288549B2 (en) 2001-06-08 2002-06-04 Heterocyclic compounds, method for preparing same and use thereof as medicines, in particular as antibacterial agents
US11/810,981 Expired - Fee Related US8148540B2 (en) 2001-06-08 2007-06-07 Heterocyclic compounds, their preparation and their use as medicaments, in particular as anti-bacterial agents

Family Applications After (1)

Application Number Title Priority Date Filing Date
US11/810,981 Expired - Fee Related US8148540B2 (en) 2001-06-08 2007-06-07 Heterocyclic compounds, their preparation and their use as medicaments, in particular as anti-bacterial agents

Country Status (15)

Country Link
US (2) US7288549B2 (ja)
EP (2) EP1798231A3 (ja)
JP (1) JP4509551B2 (ja)
AR (1) AR036091A1 (ja)
AT (1) ATE359286T1 (ja)
CA (1) CA2449830C (ja)
CY (1) CY1106801T1 (ja)
DE (1) DE60219469T2 (ja)
DK (1) DK1399444T3 (ja)
ES (1) ES2284938T3 (ja)
FR (1) FR2825705B1 (ja)
IL (1) IL158756A0 (ja)
MX (1) MXPA03011039A (ja)
PT (1) PT1399444E (ja)
WO (1) WO2002100860A2 (ja)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050020572A1 (en) * 2002-01-28 2005-01-27 Aventis Pharma S.A. Heterocyclic compounds as inhibitors of beta-lactamases
US20070299108A1 (en) * 2001-06-08 2007-12-27 Aventis Pharma S.A. New heterocyclic compounds, their preparation and their use as medicaments, in particular as anti-bacterial agents
US20090018329A1 (en) * 2002-12-06 2009-01-15 Novexel Novel heterocyclic compounds, their preparation and their use as medicaments, in particular as antibacterials and beta-lactamase inhibitors
US20100016315A1 (en) * 2006-10-23 2010-01-21 Masato Yoshida Iminopyridine Derivative and Use Thereof
US20100197928A1 (en) * 2007-09-14 2010-08-05 Novexel Method for preparing disubstituted piperidine and intermediates
US20110034464A1 (en) * 2008-04-23 2011-02-10 Takeda Pharmaceutical Company Limited Iminopyridine derivatives and use thereof
US20110039846A1 (en) * 2008-04-23 2011-02-17 Takeda Pharmaceutical Company Limited Iminopyridine derivatives and use thereof
US20110039892A1 (en) * 2008-04-23 2011-02-17 Takeda Pharmaceutical Company Limited Iminopyridine derivative and use thereof
US8487093B2 (en) 2008-01-18 2013-07-16 Merck Sharp & Dohme Corp. β-lactamase inhibitors
CN103910676A (zh) * 2013-01-04 2014-07-09 华东师范大学 一种多取代四氢异喹啉衍生物的合成方法
US10065957B2 (en) 2016-09-28 2018-09-04 Novartis Ag Beta-lactamase inhibitors

Families Citing this family (44)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2844273B1 (fr) * 2002-09-05 2008-04-04 Aventis Pharma Sa Nouveaux composes heterocycliques, procede et intermediaires de preparation et utilisation comme medicament, notamment comme inhibiteurs de beta-lactamases et anti-bacteriens.
FR2848210B1 (fr) * 2002-12-06 2007-10-19 Aventis Pharma Sa Nouveaux composes heterocycliques, leur preparation et leur utilisation comme medicaments, notamment comme anti-bacteriens et inhibiteurs de beta-lactamases
DE102004004974A1 (de) * 2004-01-31 2005-08-18 Aventis Pharma Deutschland Gmbh Thieno-Iminosäure-Derivate als Inhibitoren von Matrix-Metalloproteinasen
DE102005002500A1 (de) 2005-01-19 2006-07-27 Sanofi-Aventis Deutschland Gmbh Tetrahydrofuranderivate als Inhibitoren von Matrix-Metalloproteinasen
US7956050B2 (en) 2005-07-15 2011-06-07 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydrobenzazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
FR2914923B1 (fr) * 2007-04-12 2013-06-14 Novexel Nouveaux composes heterocycliques azotes,leur preparation et leur utilisation comme medicaments antibacteriens.
FR2916444B1 (fr) * 2007-05-25 2011-02-11 Sanofi Aventis Procede de preparation de n-carboxyanhydride enantiomeriquement enrichi.
FR2936798B1 (fr) * 2008-10-03 2012-09-28 Novexel Nouveaux composes heterocycliques azotes, leur preparation et leur utilisation comme medicaments antibacteriens.
FR2937034B1 (fr) * 2008-10-10 2012-11-23 Novexel Nouveaux composes heterocycliques azotes, leur preparation et leur utilisation comme medicaments antibacteriens
US8410117B2 (en) 2010-03-26 2013-04-02 Hoffmann-La Roche Inc. Imidazopyrimidine derivatives
US8772490B2 (en) 2010-12-22 2014-07-08 Meiji Seika Pharma Co., Ltd. Optically active diazabicyclooctane derivatives and process for preparing the same
US8853237B2 (en) 2010-12-30 2014-10-07 Vanderbilt University Naphthyridinone analogs as mGluR5 positive allosteric modulators
WO2012097182A1 (en) * 2011-01-12 2012-07-19 Vanderbilt University Dihydronaphthyridinyl(organo)methanone analogs as positive allosteric mglur5 modulators
US9505761B2 (en) 2011-12-02 2016-11-29 Fedora Pharmaceuticals Inc. Bicyclic compounds and their use as antibacterial agents and beta-lactamase inhibitors
US8796257B2 (en) 2011-12-02 2014-08-05 Naeja Pharmaceutical Inc. Bicyclic compounds and their use as antibacterial agents and β-lactamase inhibitors
JP5881514B2 (ja) * 2012-04-09 2016-03-09 株式会社トクヤマ アミン誘導体の製造方法
NZ701959A (en) * 2012-05-30 2016-07-29 Meiji Seika Pharma Co Ltd Novel β-lactamase inhibitor and method for producing same
UA111925C2 (uk) 2012-12-11 2016-06-24 Федора Фармасьютікалз Інк. БІЦИКЛІЧНІ СПОЛУКИ ТА ЇХ ВИКОРИСТАННЯ ЯК АНТИБАКТЕРІАЛЬНИХ АГЕНТІВ ТА ІНГІБІТОРІВ β-ЛАКТАМАЗИ
WO2014141132A1 (en) * 2013-03-14 2014-09-18 Naeja Pharmaceutical Inc. NEW HETEROCYCLIC COMPOUNDS AND THEIR USE AS ANTIBACTERIAL AGENTS AND β-LACTAMASE INHIBITORS
NZ718009A (en) 2013-09-24 2018-03-23 Meiji Seika Pharma Co Ltd Process for producing diazabicyclooctane derivative and intermediate thereof
EP3067355B1 (en) 2013-10-08 2020-12-16 Meiji Seika Pharma Co., Ltd. Crystals of diazabicyclooctane derivative and production method for crystals of diazabicyclooctane derivative
HUE044061T2 (hu) * 2014-11-17 2019-09-30 Entasis Therapeutics Ltd Kombinációs terápia rezisztens bakteriális fertõzések kezelésére
SG11201704576SA (en) 2014-12-05 2017-07-28 Meiji Seika Pharma Co Ltd Method for producing crystals of diazabicyclooctane derivative and stable lyophilized preparation
EP3075381A1 (en) * 2015-04-03 2016-10-05 Mutabilis Heterocyclic compounds and their use in preventing or treating bacterial infections
TW201639854A (zh) * 2015-04-03 2016-11-16 木塔比利斯公司 雜環化合物及其用於預防或治療細菌感染的用途
EP3184529A1 (en) 2015-12-23 2017-06-28 Mutabilis Heterocyclic compounds and their use in preventing or treating bacterial infections
AU2017325863B2 (en) * 2016-09-16 2021-08-19 Entasis Therapeutics Limited Beta-lactamase inhibitor compounds
EP3300736B1 (en) * 2016-09-30 2021-05-05 Mutabilis Composition comprising antibiotic compound and an heterocyclic compound and their use in preventing or treating bacterial infections
CN108239089B (zh) * 2016-12-27 2020-05-22 浙江医药股份有限公司新昌制药厂 一种阿维巴坦钠的合成方法
WO2018129008A1 (en) 2017-01-04 2018-07-12 Entasis Therapeutics Inc. Compounds and methods for treating bacterial infections
EP3357924A1 (en) * 2017-02-06 2018-08-08 Mutabilis Novel heterocyclic compounds and their use in preventing or treating bacterial infections
EA037916B1 (ru) * 2017-02-08 2021-06-07 Энтасис Терапеутикс Лимитед Соединения-ингибиторы бета-лактамаз
DK3630111T3 (en) 2017-05-08 2022-03-14 Entasis Therapeutics Inc Compounds and methods for treating bacterial infections
CN109400521B (zh) * 2017-08-18 2020-05-08 新发药业有限公司 一种改进的5r-苄氧氨基哌啶-2s-甲酸酯、其草酸盐的制备方法
CN109678855B (zh) 2017-10-18 2020-07-17 新发药业有限公司 一种阿维巴坦中间体的制备方法
CN109678856B (zh) 2017-10-18 2020-09-25 新发药业有限公司 一种阿维巴坦中间体的制备方法
CN109956941B (zh) 2017-12-25 2020-08-04 新发药业有限公司 一种阿维巴坦的简便制备方法
CN108276408B (zh) * 2018-04-19 2020-09-29 上海皓元医药股份有限公司 一种曲贝替定的中间体及其制备方法和用途
EP3604309A1 (en) 2018-07-30 2020-02-05 Mutabilis Heterocyclic compounds and their use in preventing or treating bacterial infections
EP3604315A1 (en) * 2018-07-30 2020-02-05 Mutabilis Heterocyclic compounds and their use in preventing or treating bacterial infections
US20230365561A1 (en) 2020-09-01 2023-11-16 Ningxia Academy Of Agricul Ture And Forestry Sciences Beta-lactamase inhibitors and their preparation
CN111978321A (zh) * 2020-09-22 2020-11-24 海南梵圣生物科技有限公司 一种4-Boc-2,5,6,7-四氢吡唑并[4,3-b]吡啶及其衍生物的制备方法
WO2022233181A1 (en) 2021-05-07 2022-11-10 Ningxia Academy Of Agriculture And Forestry Sciences Sulfonylamidine substituted compounds and their use as beta-lactamase inhibitors
WO2024227071A1 (en) * 2023-04-26 2024-10-31 Entasis Therapeutics Limited Synthesis of durlobactam

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990015058A1 (en) * 1989-06-09 1990-12-13 The Upjohn Company Heterocyclic amines having central nervous system activity
JPH05339263A (ja) * 1992-06-08 1993-12-21 Wakunaga Pharmaceut Co Ltd ジヒドロピリジン誘導体
EP0702004A2 (de) * 1994-09-15 1996-03-20 Ciba-Geigy Ag 2,9-Diamino- und 2-amino-8-carbamoyl-4-hydroxy-alkansäureamid-derivative
WO1996029327A1 (en) * 1995-03-18 1996-09-26 Novartis Ag Trypsin and thrombin inhibitors
WO1997023484A1 (en) * 1995-12-22 1997-07-03 Astra Aktiebolag New compounds
WO1999001434A1 (en) * 1997-07-02 1999-01-14 Bristol-Myers Squibb Company Inhibitors of farnesyl protein transferase
WO1999016442A2 (en) * 1997-09-30 1999-04-08 Pharmacia & Upjohn Company Sustained release tablet formulation to treat parkinson disease
WO1999052875A1 (en) * 1998-04-08 1999-10-21 Takeda Chemical Industries, Ltd. Amine compounds, their production and their use as somatostatin receptor antagonists or agonists
WO2000037458A1 (en) * 1998-12-18 2000-06-29 Schering Corporation Farnesyl protein transferase inhibitors
WO2001025228A1 (en) * 1999-10-07 2001-04-12 Tadeka Chemical Industries, Ltd. Amine derivatives
WO2001079206A1 (en) * 2000-04-18 2001-10-25 Sumitomo Pharmaceuticals Company, Limited Tricyclic quinazolinediones
WO2002067937A1 (en) * 2001-02-22 2002-09-06 School Of Pharmacy, University Of London Indoline and tetrahydro-quinolines as prodrugs for tumour treatment

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3654282A (en) * 1969-08-21 1972-04-04 Houde Lab 1 2 3 4-tetrahydro-isoquinoline 1-carboxylic acids
US3629265A (en) * 1969-10-30 1971-12-21 Hoffmann La Roche 7-halo-4-isoquinolones
DK0724587T3 (da) * 1993-09-29 2003-01-06 Nabi Nukleosider og nukleotider med forstørrede ringe
ATE177099T1 (de) * 1993-12-29 1999-03-15 Pfizer Diazabicyclische neurokinin antagonisten
GB9818731D0 (en) * 1998-08-27 1998-10-21 Univ Portsmouth Compounds
US20040043953A1 (en) * 2000-12-22 2004-03-04 Markus Pompejus Genes of corynebacterium
FR2825705B1 (fr) * 2001-06-08 2005-05-20 Aventis Pharma Sa Nouveaux composes heterocycliques, leur preparation et leur utilisation comme medicaments, notamment comme anti-bacteriens

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990015058A1 (en) * 1989-06-09 1990-12-13 The Upjohn Company Heterocyclic amines having central nervous system activity
JPH05339263A (ja) * 1992-06-08 1993-12-21 Wakunaga Pharmaceut Co Ltd ジヒドロピリジン誘導体
EP0702004A2 (de) * 1994-09-15 1996-03-20 Ciba-Geigy Ag 2,9-Diamino- und 2-amino-8-carbamoyl-4-hydroxy-alkansäureamid-derivative
WO1996029327A1 (en) * 1995-03-18 1996-09-26 Novartis Ag Trypsin and thrombin inhibitors
WO1997023484A1 (en) * 1995-12-22 1997-07-03 Astra Aktiebolag New compounds
WO1999001434A1 (en) * 1997-07-02 1999-01-14 Bristol-Myers Squibb Company Inhibitors of farnesyl protein transferase
WO1999016442A2 (en) * 1997-09-30 1999-04-08 Pharmacia & Upjohn Company Sustained release tablet formulation to treat parkinson disease
WO1999052875A1 (en) * 1998-04-08 1999-10-21 Takeda Chemical Industries, Ltd. Amine compounds, their production and their use as somatostatin receptor antagonists or agonists
WO2000037458A1 (en) * 1998-12-18 2000-06-29 Schering Corporation Farnesyl protein transferase inhibitors
WO2001025228A1 (en) * 1999-10-07 2001-04-12 Tadeka Chemical Industries, Ltd. Amine derivatives
WO2001079206A1 (en) * 2000-04-18 2001-10-25 Sumitomo Pharmaceuticals Company, Limited Tricyclic quinazolinediones
WO2002067937A1 (en) * 2001-02-22 2002-09-06 School Of Pharmacy, University Of London Indoline and tetrahydro-quinolines as prodrugs for tumour treatment

Non-Patent Citations (11)

* Cited by examiner, † Cited by third party
Title
Booker-Milburn et al., Azabenzocycloheptenones. Part 20. Synthesis and Utilisation of 4-amino-1,2,3,4-tetrahydro-1(1H)-benzazepines, Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry, 1997, vol. 21, pp. 3261-3273. *
Elliott et al., Syntheses and Stereochemistry of 4-Hydroxytetrahydroisoquinolines in teh 1-Benzyl and 1-Phenethyl Series. Efficient Routes to Isopavines and Homoisopavines, Tetrahedron Letters, 1980, Vol. 21, No. 48, pp. 4633-4636. *
Heier et al., An Asymmetric Synthesis of (R)-5,6-dihydro -5-(methylamino)-4H-imidazo-[4,5,1-ij]quinolin-2(1H)-one and its [2-14C]- and [6,7-3H2]-labeled Forms, Journal of Labelled Compounds & Radiopharmaceuticals (1996), vol. 38, No. 12, pp. 1087-1098. *
Heier et al., Synthesis and Biological Activities of (R)-5,6-dihydro-N,N-dimethyl-4H-imidazol[4,5,1-ij]quinolin-5-amine and Its Metabolites, Journal of Medicinal Chemistry, 1997, vol. 40, No. 5, pp. 639-646. *
Moon et al., Dopaminergic and Serotonergic Activities of Imidaoquinolinones and Related Compounds, Journal of Medicinal Chemistry, 1992, vol. 35, No. 6, pp. 1076-1092. *
Moon et al., Medicinal Chemistry of Imidazoquinolinone Dopamine Receptor Agonists, Drug Design and Discovery, 1993, vol. 9, No. 3-4, pp. 313-322. *
Moon et al., Synthesis of Tritium-labeled (R)-5-(di[2,3-3H2]propylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one and (R)-5-([2,3-3H2]propylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one, Journal of Labelled Compounds and Radiopharmaceuticals, 1992, vol. 31, No. 11, pp. 933-943. *
Romero et al., Oxidative Cyclization of Acyclic Ureas With Bis(trifluoroacetoxy)iodo Benzene to Generate N-Substituted 2-Benzimidazolinones, Tetrahedron Letters, Apr. 1, 1996, vol. 37, No. 14, pp. 2361-2364. *
Shiotani et al., The Diazabenzobicyclo[3.3.1]nonane System. I. Synthesis of 3,4,5,6-tetrahydro-2H-1,5-methanobenzo[g][1,4]diazocine and Its Derivatives, Chem. Pharm. Bull., 1964, vol. 12, No. 6, pp. 647-651. *
Tirk et al., Hydroxyminoisoquinolin-3(2H)-ones, VI Synthesis and Biological Activity of Some Aminoisoquinoline Derivatives, Acta Chimica Hungarica, 1987, vol. 124, No. 2, pp. 195-207. *
Zhou et al., Studies Directed to the Total Synthesis of ET 743 and Analogues Thereof: An Expeditious Route to the ABFGH Subunit, Organic Letters, 2002, vol. 4, No. 1, pp. 43-46. *

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8148540B2 (en) * 2001-06-08 2012-04-03 Astrazeneca Heterocyclic compounds, their preparation and their use as medicaments, in particular as anti-bacterial agents
US20070299108A1 (en) * 2001-06-08 2007-12-27 Aventis Pharma S.A. New heterocyclic compounds, their preparation and their use as medicaments, in particular as anti-bacterial agents
US20090215747A1 (en) * 2002-01-28 2009-08-27 Aventis Pharma S.A. Heterocyclic compounds as inhibitors of beta-lactamases
US7612087B2 (en) 2002-01-28 2009-11-03 Novexel Heterocyclic compounds as inhibitors of beta-lactamases
US20100048528A1 (en) * 2002-01-28 2010-02-25 Novexel Heterocyclic compounds as inhibitors of beta-lactamases
US20050020572A1 (en) * 2002-01-28 2005-01-27 Aventis Pharma S.A. Heterocyclic compounds as inhibitors of beta-lactamases
US20090018329A1 (en) * 2002-12-06 2009-01-15 Novexel Novel heterocyclic compounds, their preparation and their use as medicaments, in particular as antibacterials and beta-lactamase inhibitors
US20100016315A1 (en) * 2006-10-23 2010-01-21 Masato Yoshida Iminopyridine Derivative and Use Thereof
US8470859B2 (en) 2006-10-23 2013-06-25 Takeda Pharmaceutical Company Limited Iminopyridine derivative and use thereof
US8288553B2 (en) 2007-09-14 2012-10-16 Alain Priour Method for preparing disubstituted piperidine and intermediates
US20100197928A1 (en) * 2007-09-14 2010-08-05 Novexel Method for preparing disubstituted piperidine and intermediates
US8487093B2 (en) 2008-01-18 2013-07-16 Merck Sharp & Dohme Corp. β-lactamase inhibitors
US20110034464A1 (en) * 2008-04-23 2011-02-10 Takeda Pharmaceutical Company Limited Iminopyridine derivatives and use thereof
US20110124876A1 (en) * 2008-04-23 2011-05-26 Takeda Pharmaceutical Company Limited Iminopyridine derivatives and use thereof
US7982044B2 (en) 2008-04-23 2011-07-19 Takeda Pharmaceutical Company Limited Iminopyridine derivatives and use thereof
US7985863B2 (en) 2008-04-23 2011-07-26 Takeda Pharmaceutical Company Limited Iminopyridine derivatives and uses thereof
US7985862B2 (en) 2008-04-23 2011-07-26 Takeda Pharmaceutical Company Limited Iminopyridine derivatives and use thereof
US20110039846A1 (en) * 2008-04-23 2011-02-17 Takeda Pharmaceutical Company Limited Iminopyridine derivatives and use thereof
US20110039892A1 (en) * 2008-04-23 2011-02-17 Takeda Pharmaceutical Company Limited Iminopyridine derivative and use thereof
US20110124874A1 (en) * 2008-04-23 2011-05-26 Takeda Pharmaceutical Company Limited Iminopyridine derivatives and use thereof
US8481569B2 (en) 2008-04-23 2013-07-09 Takeda Pharmaceutical Company Limited Iminopyridine derivatives and use thereof
US20110124875A1 (en) * 2008-04-23 2011-05-26 Takeda Pharmaceutical Company Limited Iminopyridine derivatives and uses thereof
CN103910676A (zh) * 2013-01-04 2014-07-09 华东师范大学 一种多取代四氢异喹啉衍生物的合成方法
CN103910676B (zh) * 2013-01-04 2015-11-18 华东师范大学 一种多取代四氢异喹啉衍生物的合成方法
US10065957B2 (en) 2016-09-28 2018-09-04 Novartis Ag Beta-lactamase inhibitors
US10597396B2 (en) 2016-09-28 2020-03-24 Novartis Ag Beta-lactamase inhibitors

Also Published As

Publication number Publication date
CA2449830C (en) 2012-11-27
AR036091A1 (es) 2004-08-11
EP1399444B1 (fr) 2007-04-11
JP2005518333A (ja) 2005-06-23
IL158756A0 (en) 2004-05-12
CY1106801T1 (el) 2012-05-23
PT1399444E (pt) 2007-05-31
JP4509551B2 (ja) 2010-07-21
DE60219469T2 (de) 2007-11-29
FR2825705A1 (fr) 2002-12-13
EP1798231A2 (fr) 2007-06-20
US20070299108A1 (en) 2007-12-27
US8148540B2 (en) 2012-04-03
CA2449830A1 (en) 2002-12-19
WO2002100860A3 (fr) 2003-11-20
ES2284938T3 (es) 2007-11-16
US20050245505A1 (en) 2005-11-03
ATE359286T1 (de) 2007-05-15
FR2825705B1 (fr) 2005-05-20
MXPA03011039A (es) 2004-03-19
EP1798231A3 (fr) 2008-02-27
WO2002100860A2 (fr) 2002-12-19
DE60219469D1 (de) 2007-05-24
DK1399444T3 (da) 2007-06-04
EP1399444A2 (fr) 2004-03-24

Similar Documents

Publication Publication Date Title
US7288549B2 (en) Heterocyclic compounds, method for preparing same and use thereof as medicines, in particular as antibacterial agents
US7112592B2 (en) Azabicyclic compounds, preparation thereof and use as medicines, in particular as antibacterial agents
US7439253B2 (en) Heterocyclic compounds, their preparation and their use as medicaments, in particular as antibacterials and beta-lactamase inhibitors
DE60215494T2 (de) Bicyclische, stickstoffhaltige heterocyclische derivate zur verwendung als antibakterielle mittel
US20050085494A1 (en) Aminopiperidine compounds, process for their preparation, and pharmaceutical compositions containing them
TWI403323B (zh) 新穎的含氮雜環化合物其製備及作為抗菌藥之用途
US20070254872A1 (en) Antibacterial Agents
JP4954477B2 (ja) 新規複素環化合物、それらの調製、ならびに薬剤として、特に抗菌剤およびβ−ラクタマーゼ阻害剤としてのそれらの使用
WO2004096982A2 (en) Antibacterial agents
EP1664062A1 (en) Isothiazoloquinolones and related compounds as anti-infective agents
US20060235041A1 (en) New isothiazoloquinolones and related compounds as anti-infective agents
CA1281713C (en) Process for preparing new penem compounds
EP0302372B1 (en) Naphthyridine antianaerobic compounds
KR970002641B1 (ko) 퀴놀린 카르복실산의 유도체
PL143943B1 (en) Method of obtaining novel beta-lactam esters of 6-alpha- and 6-beta-/aminomethyl/penicillanic acid 1,1-dioxide
JPS60252460A (ja) アゼチジノン誘導体

Legal Events

Date Code Title Description
AS Assignment

Owner name: AVENTIS PHARMA S.A., FRANCE

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:ASZODI, J.;LAMPILAS, M.;MUSICKI, B.;AND OTHERS;REEL/FRAME:015695/0934;SIGNING DATES FROM 20040122 TO 20040308

AS Assignment

Owner name: NOVEXEL,FRANCE

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:AVENTIS PHARMA S.A.;REEL/FRAME:018545/0842

Effective date: 20060202

Owner name: NOVEXEL, FRANCE

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:AVENTIS PHARMA S.A.;REEL/FRAME:018545/0842

Effective date: 20060202

STCF Information on status: patent grant

Free format text: PATENTED CASE

FPAY Fee payment

Year of fee payment: 4

FPAY Fee payment

Year of fee payment: 8

AS Assignment

Owner name: ENTASIS THERAPEUTICS LIMITED, UNITED KINGDOM

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:ASTRA ZENECA HOLDING FRANCE;REEL/FRAME:037266/0923

Effective date: 20150511

Owner name: ASTRA ZENECA HOLDING FRANCE, FRANCE

Free format text: MERGER;ASSIGNOR:NOVEXEL;REEL/FRAME:037273/0896

Effective date: 20121221

FEPP Fee payment procedure

Free format text: MAINTENANCE FEE REMINDER MAILED (ORIGINAL EVENT CODE: REM.); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

LAPS Lapse for failure to pay maintenance fees

Free format text: PATENT EXPIRED FOR FAILURE TO PAY MAINTENANCE FEES (ORIGINAL EVENT CODE: EXP.); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

STCH Information on status: patent discontinuation

Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362

FP Lapsed due to failure to pay maintenance fee

Effective date: 20191030